Currently, there are 7.7 million smokeless tobacco users in the U.S. Smokeless tobacco use has been associated with increased risk of oral pathologies (including oral cancer), pancreatic cancer, diabetes and other components of the metabolic syndrome, fetal toxicity and possibly cardiovascular disease. The extent of these health risks may be associated with the amount of toxicants in these products and the extent of exposure to these toxicants. Research has shown wide variability in carcinogens as well as nicotine in these products. The WHO Framework Convention on Tobacco Control and the proposed FDA legislative bill for tobacco product regulation have provisions that would require tobacco companies to reduce or eliminate harmful toxicants and to reduce levels of nicotine. However, very little research is available to guide decision makers on the impact of reducing toxicants and nicotine nor do we completely understand factors other than product toxicity that are associated with the extent of toxicant exposure. Two studies are proposed with the following goals: 1) Study 1 will examine brands of U.S. smokeless tobacco (ST) products that contain different levels of tobacco specific nitrosamines (TSNAs), other carcinogens and nicotine on existing and novel biomarkers of exposure and effect. In addition, this study will comprehensively determine factors that moderate the extent of exposure other than the levels of toxicants in these products. These factors include individual, social and environmental influences. Subjects will be recruited from 3 different regions in the U.S. and will be assessed on two different occasions. This study will contribute new information on critical factors associated with toxicant exposure. 2) Study 2 will determine the effects of switching ST users to lower TSNA and high, moderate or low nicotine ST products on pattern of use, biomarkers of exposure and toxicity, and facilitation of abstinence. Subjects will undergo measurements during use of their usual brand of smokeless tobacco and then switch to the assigned product for 12 weeks, with follow-up at week 13 and 26. This study would demonstrate the feasibility and impact of switching ST users to less toxic ST products. Together, these studies will help to guide important policy decisions to reduce the toll of tobacco-related disease.